Thursday, 10 March 2016
ME Association to fund fourth study into the role of the mitochondria in ME/CFS
We are pleased to announce that our Ramsay Research Fund is about to start funding another research study relating to the role of mitochondria in ME/CFS. This research grant has been given to Dr Karl Morten and Professor Joanna Poulton at the University of Oxford.
The following description of the background to the Oxford research and what will it involve has been prepared by Dr Karl Morten:
Is aberrant mitochondrial function a major player in CFS/ME?
Mitochondria are well known for their role as the ‘power house of the cell’. But they also have a diverse range of other functions.
These include a role in programming cell death, synthesis of cellular building blocks, cell-signalling and more recently a potential role in cellular immunity (West et al 2015).
Control of mitochondrial number, quality and structure is a highly regulated process varying between cells and tissues.
The fatigue seen in CFS/ME patients and the post-exertional malaise observed in the majority of patients has led to the proposal that a failure in the energy generation/supply system at a cellular level may play a role in the disease.
Over the last 20-30 years, attempts by researchers using techniques successfully applied to identify mitochondrial defects in patients with genetic defects in the mitochondrial respiratory chain have consistently failed to identify mitochondrial abnormalities in CFS/ME patients.
Between, 2009-2013 a series of papers by Booth/Myhill et al [2-4] have demonstrated an interesting correlation between the level of mitochondrial dysfunction in a specific type of white blood cell called a neutrophil and the severity of disease in ME/CFS patients.
In addition to measuring total cellular energy in the form of a chemical called adenosine triphosphate (ATP) the authors use novel approaches to measure the ability of mitochondria to regenerate ATP following depletion of mitochondria ATP with the electron transfer chain (ETC) inhibitor sodium azide.
Such an approach is claimed to be a major advance on current approaches which just measure steady state levels of ATP and adenosine diphosphate (ADP) in isolated organelles or whole cells.
As steady state ATP levels are a consequence of supply and demand they do not always reflect the ability of mitochondria to generate ATP.
MEA project grant (5 months):
Establishing protocols to assess mitochondrial function in Neutrophils and Monocytes from ME/CFS patients.
The current pilot study is to set up the tests required to assess mitochondrial function in blood samples from ME/CFS patients.
For this we will use cell models with known mitochondrial dysfunction and bio-energetic impairment to both validate and improve on the tests developed by Acumen [2-4].
Our goal is to develop a method to assess mitochondrial function compatible with the widely used Seahorse Biosciences metabolic flux analyzer and plate based fluorescent probe oxygen and pH measuring platforms.
This will make the blood tests more globally accessible to a wide range of researchers allowing a more universal validation of the findings of Booth/Myhill.
Other MEA RRF research involving mitochondria in ME/CFS.
The MEA Ramsay Research Fund has been funding, or co-funding, three other research projects involving mitochondrial function and testing mitochondrial function:
1 COMPARISON OF RESULTS FROM A COMMERCIAL AND NHS BLOOD TEST TO ASSESS MITOCHONDRIAL FUNCTION
This study is comparing the results of a commercial blood test for mitochondrial function that has been developed by Dr Sarah Myhill and colleagues with the results from an international and widely accepted test of mitochondrial function that has a long and successful track record in clinical diagnosis and research of muscle disease particularly in the UK.
The aim is to determine the efficacy of each set of tests in relation to ME/CFS. In the exciting case that a synergy between the two diagnostic approaches exists, it is hoped that this preliminary study will promote an investigation into a more inclusive and highly resolved analytical technique for metabolic testing of people with ME/CFS.
Lead researcher: Dr Sarah Jayne Boulton
RRF investment = £21,305
More information here: www.meassociation.org.uk/2015/07/new-award-from-the-mea-ramsay-research-fund-for-further-mitochondrial-research-20-july-2015/
2 ABNORMALITIES IN MITOCHONDRIAL FUNCTION IN SKELETAL MUSCLE (CO-FUNDED WITH THE MEDICAL RESEARCH COUNCIL)
Employing new technology, this research aims to demonstrate that skeletal muscle mitochondria are dysfunctional and cause the muscle fatigue experienced in ME/CFS:
‘The dysfunctional mitochondria then activate a process which leads to a chronic, low grade inflammation, commonly reported in patients with CFS, which in turn results in further mitochondrial abnormalities and the establishment of a vicious circle of events. Understanding the processes by which muscle fatigue occurs will lead to optimal interventions that break this vicious circle and improve muscle function and wellbeing of individuals.’ Extract taken from: MRC CFS/ME Current Projects
Preliminary results from the study were published in a recent paper: ‘The Role of Cytokines in Muscle Fatigue in Patients with Chronic Fatigue Syndrome’, The FASEB Journal, April 2015.
The authors recruited 100 untreated patients with CFS and 100 age and sex matched healthy controls, and concluded:
‘…a sub-group of patients with CFS may have low level inflammation and analyses are underway to further characterise other inflammatory markers in serum and muscle of these patients and to determine whether such changes could affect indices of muscle function or central fatigue.’
Lead researcher: Professor Anne McArdle
This research is being jointly funded with the Medical Research Council
RRF investment = £30,000
3 PATTERNS OF MITOCHONDRIAL DNA VARIATION
This is an 18-month study that began in May 2014 and seeks to determine if patterns of mitochondrial DNA variation in ME/CFS are different than in healthy controls.
At the launch of the initiative, Dr Joanna Elson commented:
“Mitochondria are the powerhouses of the cell, and mitochondrial DNA provides the codes for proteins that are essential for energy production. We want to see if patients with ME/CFS have different patterns of mitochondrial DNA variation that could affect a person’s chances of succumbing to ME/CFS, or act as a barrier to recovery.”
Lead researcher: Dr Joanna Elson
This research is being funded by Action for M.E.
RRF donation = £5,000
More information on the work of the MEA Ramsay Research Fund:
Easy-to-understand information on mitochondria and mitochondrial disease:
1. West A.P., Khoury-Hanold, W, Staron M, Tal M.C, Pineda C.M, Lang S.M, Bestwick M, Duguay B.A, Raimundo N, MacDuff D.A, Kaech S.M, Smiley J.R, Means R.E, Iwasaki A and Shadel G.S. Mitochondrial DNA stress primes the antiviral innate immune response. Nature. 2015 Apr 23; 520(7548):553-7
2. Booth, N.E., S. Myhill, and J. McLaren-Howard, Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Int J Clin Exp Med, 2012. 5(3): p. 208-20.
3. Myhill, S., N.E. Booth, and J. McLaren-Howard, Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med, 2009. 2(1): p. 1-16.
4. Myhill, S., N.E. Booth, and J. McLaren-Howard, Targeting mitochondrial dysfunction in the treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) – a clinical audit. Int J Clin Exp Med, 2013. 6(1): p. 1-15.
Dr Charles Shepherd
Hon Medical Adviser,